Chronic bronchitis is a type of chronic obstructive pulmonary disease (COPD), and is characterized by chronic cough with sputum production. Airflow and gas exchange are significantly limited by airway inflammation, mucus hypersecretion, airway hyperresponsiveness, and eventual fibrosis of the airway walls. Asthma is similar to chronic bronchitis, though the underlying cause is often an inherent defect of airway smooth muscle or the inflammatory milieu, which makes airway smooth muscle hyperreactive. Chronic asthma can have similar airway wall thickening as in chronic bronchitis, leading to a permanent, irreversible airflow obstruction. Emphysema also is a type of COPD, and is characterized by the destruction of the lung parenchyma. This destruction of the lung parenchyma leads to a loss of elastic recoil and tethering which maintains airway patency. Because bronchioles are not supported by cartilage like the larger airways are, they have little intrinsic support and therefore are susceptible to collapse when destruction of tethering occurs, particularly during exhalation.
COPD currently affects over 15 million people in the United States alone and is currently the third leading cause of death in the country. Currently, over 90% of COPD cases are caused by inhalation of cigarette smoke. The economic and social burden of the disease is substantial and is increasing. Between about 50% and 75% of the economic burden for COPD is related to healthcare services for acute exacerbations of COPD (AECOPD). This economic burden is attributable mostly to emergency care and inpatient hospital care. AECOPD are defined by a sudden worsening of symptoms (e.g. increase in or onset of cough, wheeze, and sputum changes) that typically last for several days, up to a couple weeks. AECOPD are typically triggered by a bacterial infection, viral infection, or pollutants, which manifests quickly into airway inflammation, mucus hypersecretion, and bronchoconstriction, mucus production which cause significant airway restriction.
Despite relatively efficacious drugs (long-acting muscarinic antagonists, long-acting beta agonists, corticosteroids, and antibiotics) that treat COPD symptoms, a particular segment of patients known as “frequent exacerbators” often visit the emergency room and hospital with exacerbations and also have a more rapid decline in lung function, poorer quality of life, and greater mortality. A need exists for COPD patients to reduce the occurrence of AECOPD events.
The autonomic nervous system provides constant control over airway smooth muscle, secretory cells, and vasculature. Parasympathetic fibers are motor to bronchial smooth muscle, inhibitory to the pulmonary vessels, and secretory to the bronchial glands; and sympathetic fibers are inhibitory to the bronchial muscle, motor to the pulmonary vessels, and inhibitory to aveolar glands. Although both sympathetic and parasympathetic branches of the autonomic nervous system innervate the airways, parasympathetic branch dominates especially with respect to control of airway smooth muscle and mucus secretions. Cholinergic nerve fibers arise in the nucleus ambiguous in the brain stem and travel down the vagus nerve (right and left vagus nerves) and synapse in parasympathetic ganglia which are located within the airway wall. These parasympathetic ganglia are most numerous in the trachea and mainstem bronchi, especially near the hilus and points of bifurcations, with fewer ganglia smaller in size dispersed in distal airways. From these ganglia short post-ganglionic fibers travel to airway smooth muscle and submucosal glands. Cholinergic control of airway smooth muscle involves pre-ganglionic and post-ganglionic parasympathetic nerves releasing acetylcholine (ACh) and can be activated by airway and extra-pulmonary afferent nerves. ACh is released from post-ganglionic fibers and acts upon M1-and M3-receptors on smooth muscles and submucosal glands to cause bronchoconstriction and mucus secretion, respectively. ACh may regulate airway inflammation and airway remodeling, which may contribute to the pathophysiology of obstructive airways diseases. Therefore controlling the parasympathetic nerve signals to the lungs can control bronchoconstriction, mucus secretion, cough, and possibly inflammation and remodeling.
A wide variety of stimuli (cigarette smoke, mechanical stimuli, and other irritants) are able to elicit reflex cholinergic bronchoconstriction through activation of sensory receptors in the larynx or airways. Said sensory receptors primarily include rapidly adapting receptors (RARs) and C-Fibers, both of which have nerve endings in the epithelium. Activation of these afferent nerves causes a cholinergic reflex that is known to result in bronchoconstriction and an increase in airway mucus secretion through the activation of muscarinic receptors on airway smooth muscle cells and submucosal glands. Irritants in the airways can trigger afferent receptor nerves and set-off a reflex action initiating bronchoconstriction and mucus production, both of which are common during AECOPD events.
Anticholinergic drugs (antimuscarinic agents) such as Spiriva have been developed which are believed to bind to the muscarinic receptors on smooth muscle cells, preventing ACh from binding to those sites, resulting in a reduction in bronchoconstriction. These drugs are not completely effective for all patients (in part due to lack of compliance to treatment schedules) however, and many patients continue to have AECOPD events despite being prescribed these drugs.
Bronchial hyperreactivity (BHR) is common in COPD and is most likely caused by hypersensitivity of receptor nerve fibers, lower thresholds for reflex action initiation, and reduced natural self-limitation mechanism of ACh release. Various reports have suggested that BHR may be present in over 60% to of COPD patients. This “hyperreactivity” may be due to a “hyperreflexivity”. There are several mechanisms by which parasympathetic drive may be overactivated in inflammatory disease. Inflammation is commonly associated with overt activation and increases in excitability of vagal C-fibers in the airways that could increase reflex parasympathetic tone. Also, airway inflammation and inflammatory mediators have been found to increase synaptic efficacy and decrease action potential accommodation in bronchial parasympathetic ganglia; effects that would likely reduce their filtering function and lead to prolonged excitation. Further, airway inflammation has also been found to inhibit muscarinic M2 receptor-mediated auto-inhibition of ACh release from postganglionic nerve terminals. This would lead to a larger end-organ response (e.g. smooth muscle contraction) for a given amount of action potential discharge. Additionally, airway inflammation has been associated with phenotypic changes in the parasympathetic nervous system that could affect the balance of cholinergic contractile versus non-adrenergic non-cholinergic (NANC) relaxant innervation of smooth muscle.
In addition to smooth muscle contraction and mucus production noted above, chronic inflammation of the airways plays a central role in COPD. Even during stable COPD, increases in the number of inflammatory proteins have been described in the systemic circulation, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-8. Small but significant increases in circulating levels of both the soluble TNF receptors 55 and 75 (sTNF-R55 and sTNF-R75), IL-10 and IL-18 have also been reported in such patients. Importantly, epidemiological studies suggesting relationships between circulatory inflammatory mediators and reductions in pulmonary functions reflected by decreases in forced expiratory volume in one second (FEV1). COPD exacerbations are associated with further increases in these inflammatory markers of both bronchial and systemic inflammation over and above levels present during the stable state of the disease. A need therefore additionally exists to reduce inflammation of the airways in COPD patients.